scholarly journals Collagen density defines 3D migration of CTLs and their consequent cytotoxicity against tumor cells

2021 ◽  
Author(s):  
Renping Zhao ◽  
Xiangda Zhou ◽  
Essak S Khan ◽  
Dalia Alansary ◽  
Kim S Friedmann ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocytes ◽  
Actin Polymerization ◽  
Strongly Correlated ◽  
Microtubule Network ◽  
Collagen Matrices ◽  
Promising Target ◽  
Cytotoxic Proteins ◽  
Collagen Density ◽  
Microtubule Networks ◽  
The Impact

Solid tumors are often characterized by condensed extracellular matrix (ECM). The impact of dense ECM on cytotoxic T lymphocytes (CTL) function is not fully understood. Here, we report that CTL-mediated cytotoxicity is substantially impaired in dense collagen matrices. Although the intrinsic killing machinery including expression of cytotoxic proteins and degranulation was intact, CTL motility was substantially compromised in dense collagen. We found that for 3D CTL migration, persistence and velocity was regulated by collagen stiffness and the porosity, respectively. Interestingly, 3D CTL velocity is strongly correlated with their nuclear deformability/flexibility during migration, which is regulated by the microtubule network. Moreover, CTL migration was completely abolished by inhibition of actin polymerization and or myosin IIA. Remarkably, disruption of the microtubule-networks significantly improves the impaired migration, search efficiency, and cytotoxicity of CTLs in dense collagen. Our work suggests the microtubule network as a promising target to rescue impaired CTL killing capacity in solid tumor related scenarios.

scholarly journals Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices

2021 ◽  
Vol 12 ◽  
Author(s):  
Renping Zhao ◽  
Xiangda Zhou ◽  
Essak S. Khan ◽  
Dalia Alansary ◽  
Kim S. Friedmann ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Cytotoxic T Lymphocyte ◽  
Light Sheet ◽  
Strongly Correlated ◽  
Microtubule Inhibitor ◽  
Microtubule Network ◽  
Collagen Matrices ◽  
Light Sheet Microscopy ◽  
3D Matrix ◽  
Cytotoxic Proteins

Efficacy of cytotoxic T lymphocyte (CTL)-based immunotherapy is still unsatisfactory against solid tumors, which are frequently characterized by condensed extracellular matrix. Here, using a unique 3D killing assay, we identify that the killing efficiency of primary human CTLs is substantially impaired in dense collagen matrices. Although the expression of cytotoxic proteins in CTLs remained intact in dense collagen, CTL motility was largely compromised. Using light-sheet microscopy, we found that persistence and velocity of CTL migration was influenced by the stiffness and porosity of the 3D matrix. Notably, 3D CTL velocity was strongly correlated with their nuclear deformability, which was enhanced by disruption of the microtubule network especially in dense matrices. Concomitantly, CTL migration, search efficiency, and killing efficiency in dense collagen were significantly increased in microtubule-perturbed CTLs. In addition, the chemotherapeutically used microtubule inhibitor vinblastine drastically enhanced CTL killing efficiency in dense collagen. Together, our findings suggest targeting the microtubule network as a promising strategy to enhance efficacy of CTL-based immunotherapy against solid tumors, especially stiff solid tumors.

Analysis of the journal impact factor and related bibliometric indicators in education and educational research category

2021 ◽  
pp. 1-22
Author(s):  
Metin Orbay ◽  
Orhan Karamustafaoğlu ◽  
Ruben Miranda
Keyword(s):  
Impact Factor ◽  
Educational Research ◽  
Journal Impact Factor ◽  
Impact Factors ◽  
Bibliometric Indicators ◽  
Strongly Correlated ◽  
Starting Point ◽  
Consistent Assessment ◽  
The Impact ◽  
Journal Impact

This study analyzes the journal impact factor and related bibliometric indicators in Education and Educational Research (E&ER) category, highlighting the main differences among journal quartiles, using Web of Science (Social Sciences Citation Index, SSCI) as the data source. High impact journals (Q1) publish only slightly more papers than expected, which is different to other areas. The papers published in Q1 journal have greater average citations and lower uncitedness rates compared to other quartiles, although the differences among quartiles are lower than in other areas. The impact factor is only weakly negative correlated (r=-0.184) with the journal self-citation but strongly correlated with the citedness of the median journal paper (r= 0.864). Although this strong correlation exists, the impact factor is still far to be the perfect indicator for expected citations of a paper due to the high skewness of the citations distribution. This skewness was moderately correlated with the citations received by the most cited paper of the journal (r= 0.649) and the number of papers published by the journal (r= 0.484), but no important differences by journal quartiles were observed. In the period 2013–2018, the average journal impact factor in the E&ER has increased largely from 0.908 to 1.638, which is justified by the field growth but also by the increase in international collaboration and the share of papers published in open access. Despite their inherent limitations, the use of impact factors and related indicators is a starting point for introducing the use of bibliometric tools for objective and consistent assessment of researcher.

scholarly journals A Phantom Study to Investigate Robustness and Reproducibility of Grey Level Co-Occurrence Matrix (GLCM)-Based Radiomics Features for PET

2021 ◽  
Vol 11 (2) ◽  
pp. 535
Author(s):  
Mahbubunnabi Tamal
Keyword(s):  
Textural Features ◽  
Strongly Correlated ◽  
Segmentation Method ◽  
Diagnosis And Prognosis ◽  
Radiotracer Uptake ◽  
Positron Emission ◽  
Occurrence Matrix ◽  
The Impact ◽  
Robust To Noise

Quantification and classification of heterogeneous radiotracer uptake in Positron Emission Tomography (PET) using textural features (termed as radiomics) and artificial intelligence (AI) has the potential to be used as a biomarker of diagnosis and prognosis. However, textural features have been predicted to be strongly correlated with volume, segmentation and quantization, while the impact of image contrast and noise has not been assessed systematically. Further continuous investigations are required to update the existing standardization initiatives. This study aimed to investigate the relationships between textural features and these factors with 18F filled torso NEMA phantom to yield different contrasts and reconstructed with different durations to represent varying levels of noise. The phantom was also scanned with heterogeneous spherical inserts fabricated with 3D printing technology. All spheres were delineated using: (1) the exact boundaries based on their known diameters; (2) 40% fixed; and (3) adaptive threshold. Six textural features were derived from the gray level co-occurrence matrix (GLCM) using different quantization levels. The results indicate that homogeneity and dissimilarity are the most suitable for measuring PET tumor heterogeneity with quantization 64 provided that the segmentation method is robust to noise and contrast variations. To use these textural features as prognostic biomarkers, changes in textural features between baseline and treatment scans should always be reported along with the changes in volumes.

scholarly journals Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Andoni Garitano-Trojaola ◽  
Ana Sancho ◽  
Ralph Götz ◽  
Patrick Eiring ◽  
Susanne Walz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Actin Cytoskeleton ◽  
Myeloid Leukemia ◽  
Actin Polymerization ◽  
Cell Stiffness ◽  
Adhesion Forces ◽  
Frequent Mutations ◽  
New Perspective ◽  
The Impact ◽  
Acute Myeloid

AbstractThe presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.

Decline of contractility during ischemia-reperfusion injury: actin glutathionylation and its effect on allosteric interaction with tropomyosin

2006 ◽  
Vol 290 (3) ◽  
pp. C719-C727 ◽  
Author(s):  
Frank C. Chen ◽  
Ozgur Ogut
Keyword(s):  
Reperfusion Injury ◽  
Posttranslational Modifications ◽  
Actin Polymerization ◽  
Time Course ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Concentration ◽  
Cross Sectional ◽  
The Impact

The severity and duration of ischemia-reperfusion injury is hypothesized to play an important role in the ability of the heart subsequently to recover contractility. Permeabilized trabeculae were prepared from a rat model of ischemia-reperfusion injury to examine the impact on force generation. Compared with the control perfused condition, the maximum force (Fmax) per cross-sectional area and the rate of tension redevelopment of Ca2+-activated trabeculae fell by 71% and 44%, respectively, during ischemia despite the availability of a high concentration of ATP. The reduction in Fmax with ischemia was accompanied by a decline in fiber stiffness, implying a drop in the absolute number of attached cross bridges. However, the declines during ischemia were largely recovered after reperfusion, leading to the hypothesis that intrinsic, reversible posttranslational modifications to proteins of the contractile filaments occur during ischemia-reperfusion injury. Examination of thin-filament proteins from ischemic or ischemia-reperfused hearts did not reveal proteolysis of troponin I or T. However, actin was found to be glutathionylated with ischemia. Light-scattering experiments demonstrated that glutathionylated G-actin did not polymerize as efficiently as native G-actin. Although tropomyosin accelerated the time course of native and glutathionylated G-actin polymerization, the polymerization of glutathionylated G-actin still lagged native G-actin at all concentrations of tropomyosin tested. Furthermore, cosedimentation experiments demonstrated that tropomyosin bound glutathionylated F-actin with significantly reduced cooperativity. Therefore, glutathionylated actin may be a novel contributor to the diverse set of posttranslational modifications that define the function of the contractile filaments during ischemia-reperfusion injury.

scholarly journals Subtle changes in crosslinking drive diverse anomalous transport characteristics in actin-microtubule networks

2020 ◽  
Author(s):  
Sylas Anderson ◽  
Jonathan Garamella ◽  
Ryan McGorty ◽  
Rae Robertson-Anderson
Keyword(s):  
Intracellular Transport ◽  
Single Particle Tracking ◽  
Anomalous Transport ◽  
Brownian Diffusion ◽  
Complex Environments ◽  
Materials Engineering ◽  
Microtubule Networks ◽  
Non Gaussian ◽  
Fluid Rheology ◽  
The Impact

Abstract Anomalous diffusion in crowded and complex environments is widely studied due to its importance in intracellular transport, fluid rheology and materials engineering. Specifically, diffusion through the cytoskeleton, a network comprised of semiflexible actin filaments and rigid microtubules that interact both sterically and via crosslinking, plays a principal role in viral infection, vesicle transport and targeted drug delivery. Here, we elucidate the impact of crosslinking on particle diffusion in composites of actin and microtubules with actin-actin, microtubule-microtubule and actin-microtubule crosslinking. We analyze a suite of complementary transport metrics by coupling single-particle tracking and differential dynamic microscopy. Using these orthogonal techniques, we find that particles display non-Gaussian and non-ergodic subdiffusion that is markedly enhanced by cytoskeletal crosslinking of any type, which we attribute to suppressed microtubule mobility. However, the extent to which transport deviates from normal Brownian diffusion depends strongly on the crosslinking motif – with actin-microtubule crosslinking inducing the most pronounced anomalous characteristics – due to increased actin fluctuation heterogeneity. Our results reveal that subtle changes to actin-microtubule interactions can have dramatic impacts on diffusion in the cytoskeleton, and suggest that less mobile and more locally heterogeneous networks lead to more strongly anomalous transport.

scholarly journals Chemo-mechanical Diffusion Waves Orchestrate Collective Dynamics of Immune Cell Podosomes

2021 ◽  
Author(s):  
Ze Gong ◽  
Koen van den Dries ◽  
Alessandra Cambi ◽  
Vivek Shenoy
Keyword(s):  
Actin Polymerization ◽  
Immune Cell ◽  
Wave Dynamics ◽  
Diffusion Waves ◽  
Mechanical Diffusion ◽  
Mechanical Waves ◽  
The Individual ◽  
The Impact ◽  
Cell Mechanosensing

Immune cells, such as macrophages and dendritic cells, can utilize podosomes, actin-rich protrusions, to generate forces, migrate, and patrol for foreign antigens. In these cells, individual podosomes exhibit periodic protrusion and retraction cycles (vertical oscillations) to probe their microenvironment, while multiple podosomes arranged in clusters demonstrate coordinated wave-like spatiotemporal dynamics. However, the mechanisms governing both the individual vertical oscillations and the coordinated oscillation waves in clusters remain unclear. By integrating actin polymerization, myosin contractility, actin diffusion, and mechanosensitive signaling, we develop a chemo-mechanical model for both the oscillatory growth of individual podosomes and wave-like dynamics in clusters. Our model reveals that podosomes show oscillatory growth when the actin polymerization-associated protrusion and the signaling-associated myosin contraction occur at similar rates, while the diffusion of actin monomers within the cluster drives mesoscale coordination of individual podosome oscillations in an apparent wave-like fashion. Our model predicts the influence of different pharmacological treatments targeting myosin activity, actin polymerization, and mechanosensitive pathways, as well as the impact of the microenvironment stiffness on the wavelengths, frequencies, and speeds of the chemo-mechanical waves. Overall, our integrated theoretical and experimental approach reveals how collective wave dynamics arise due to the coupling between chemo-mechanical signaling and actin diffusion, shedding light on the role of podosomes in immune cell mechanosensing within the context of wound healing and cancer immunotherapy.

Downregulation of CCKBR Expression Inhibits the Proliferation of Gastric Cancer Cells, Revealing a Potential Target for Immunotoxin Therapy

2022 ◽  
Vol 22 ◽  
Author(s):  
Meng Li ◽  
Jiang Chang ◽  
Honglin Ren ◽  
Defeng Song ◽  
Jian Guo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Aberrant Expression ◽  
Promising Target ◽  
The Impact

Background Increased CCKBR expression density or frequency has been reported in many neoplasms. Objective We aimed to investigate whether CCKBR drives the growth of gastric cancer (GC) and its potential as a therapeutic target of immunotoxins. Methods A lentiviral interference system was used to generate CCKBR-knockdown gastric cancer cells. Cell Counting Kit-8 and clonogenic assays were used to evaluate cell proliferation. Wound-healing and cell invasion assays were performed to evaluate cell mobility. Cell cycle was analyzed by flow cytometry. Tumor growth in vivo was investigated using a heterologous tumor transplantation model in nude mice. In addition, we generated the immunotoxin FQ17P and evaluated the combining capacity and tumor cytotoxicity of FQ17P in vitro. Results Stable downregulation of CCKBR expression resulted in reduced proliferation, migration and invasion of BGC-823 and SGC-7901 cells. The impact of CCKBR on gastric cancer cells was further verified through CCKBR overexpression studies. Downregulation of CCKBR expression also inhibited the growth of gastric tumors in vivo. Furthermore, FQ17P killed CCKBR-overexpressing GC cells by specifically binding to CCKBR on the tumor cell surface. Conclusion The CCKBR protein drives the growth, migration, and invasion of gastric cancer cells, and it might be a promising target for immunotoxin therapy based on its aberrant expression, functional binding interactions with gastrin, and subsequent internalization.

scholarly journals Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation

2020 ◽  
Vol 65 (1) ◽  
pp. e01373-20
Author(s):  
Christoph H. R. Senges ◽  
Jennifer J. Stepanek ◽  
Michaela Wenzel ◽  
Nadja Raatschen ◽  
Ümran Ay ◽  
...  
Keyword(s):  
Rapid Identification ◽  
Mechanisms Of Action ◽  
Proteomic Profiling ◽  
Content Type ◽  
Bacterial Physiology ◽  
Proteomic Approach ◽  
Promising Target ◽  
New Antibiotics ◽  
Proteomic Responses ◽  
The Impact

ABSTRACTNew antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. Comparison of proteomic responses (CoPR) allows the rapid identification of antibiotics with dual mechanisms of action as shown for atypical tetracyclines. It also aids in generating hypotheses on mechanisms of action as presented for salvarsan (arsphenamine) and the antirheumatic agent auranofin, which is under consideration for repurposing. Proteomic profiling also provides insights into the impact of antibiotics on bacterial physiology through analysis of marker proteins indicative of the impairment of cellular processes and structures. As demonstrated for trans-translation, a promising target not yet exploited clinically, proteomic profiling supports chemical biology approaches to investigating bacterial physiology.

The Impact of a Video-Mediated Communication on Separated Perinatal Couples in Japan

2017 ◽  
Vol 29 (2) ◽  
pp. 202-211
Author(s):  
Ryoko Furukawa ◽  
Martha Driessnack ◽  
Eiko Kobori
Keyword(s):  
Visual Cues ◽  
Perinatal Period ◽  
Marital Relationships ◽  
Control Group ◽  
Strongly Correlated ◽  
Mediated Communication ◽  
Mixed Methods Approach ◽  
Data Collection And Analysis ◽  
Japanese Communication ◽  
The Impact

Japanese communication relies heavily on nonverbal cues and context. The purpose of this study was to examine the impact of video-mediated communication (VMC) on communication satisfaction and marital relationships in young couples separated during the perinatal period as they honor the Japanese tradition of Satogaeri Bunben. Couples were assigned to the VMC treatment group ( n = 14) or control group ( n = 13). A mixed-methods approach to data collection and analysis was used. Longitudinal quantitative analysis from the Primary Communication Inventory and Intimate Bond Measure revealed significant differences between the Husband groups. Primary Communication Inventory and Intimate Bond Measure were strongly correlated regardless of group. Qualitative analysis of participant diaries revealed the addition of visual cues helped create a sense of “virtual co-presence,” which was both positive and negative. In conclusion, VMC appears to improve communication in the separated Japanese perinatal couples, especially through the addition of visual cues provided with VMC.

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